• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Human mutation >Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance.
【24h】

Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance.

机译：胶原蛋白VI中的外显子跳跃突变很常见，可预测严重程度和遗传。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), two related conditions of differing severity. BM is a relatively mild dominantly inherited disorder characterized by proximal weakness and distal joint contractures. UCMD was originally regarded as an exclusively autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity. We and others have subsequently modified this model when we described UCMD patients with heterozygous in-frame deletions acting in a dominant-negative way. Here we report 10 unrelated patients with a UCMD clinical phenotype and de novo dominant negative heterozygous splice mutations in COL6A1, COL6A2, and COL6A3 and contrast our findings with four UCMD patients with recessively acting splice mutations and two BM patients with heterozygous splice mutations. We find that the location of the skipped exon relative to the molecular structure of the collagen chain strongly correlates with the clinical phenotype. Analysis by immunohistochemical staining of muscle biopsies and dermal fibroblast cultures, as well as immunoprecipitation to study protein biosynthesis and assembly, suggests different mechanisms each for exon skipping mutations underlying dominant UCMD, dominant BM, and recessive UCMD. We provide further evidence that de novo dominant mutations in severe UCMD occur relatively frequently in all three collagen VI chains and offer biochemical insight into genotype-phenotype correlations within the collagen VI-related disorders by showing that severity of the phenotype depends on the ability of mutant chains to be incorporated in the multimeric structure of collagen VI.
机译：编码胶原VI的基因（COL6A1，COL6A2和COL6A3）中的突变会导致Bethlem肌病（BM）和Ullrich先天性肌营养不良（UCMD），这是两个严重程度不同的相关状况。 BM是相对轻度的显性遗传性疾病，其特征是近端无力和远端关节挛缩。 UCMD最初被认为是一种常染色体隐性遗传病，可导致严重的肌肉无力，近端关节挛缩和远端松弛。当我们描述具有杂合性框内缺失且以显性负性方式起作用的UCMD患者时，我们和其他人随后修改了该模型。在这里，我们报告了10位无关联的UCMD临床表型和COL6A1，COL6A2和COL6A3的从头显性负杂合剪接突变的患者，并将我们的发现与4例隐性作用剪接突变的UCMD患者和2例杂合剪接突变的BM患者进行了对比。我们发现跳过的外显子相对于胶原蛋白链的分子结构的位置与临床表型密切相关。通过对肌肉活组织检查和皮肤成纤维细胞培养物进行免疫组织化学染色分析，以及研究蛋白质生物合成和组装的免疫沉淀，提出了外显子跳过显性UCMD，显性BM和隐性UCMD基础突变的不同机制。我们提供了进一步的证据，表明在严重的UCMD中从头显性突变在所有三个胶原VI链中都相对频繁发生，并通过显示表型的严重性取决于突变体的能力，从而提供了对胶原VI相关疾病内的基因型-表型相关性的生化研究。链被掺入胶原VI的多聚体结构中。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号